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Markus Grompe, M.D.

Biography

Dr. Grompe received his medical degree (Dr. med.) in 1982 at the University of Ulm Medical School in Germany. From 1984-1987 Dr. Grompe was trained in Pediatrics at Oregon Health Sciences University in Portland, Oregon, USA and then moved to Baylor College of Medicine in Houston, Texas. There he was a fellow sponsored by the Pediatric Scientist Training Program in the Institute for Molecular Genetics from 1987-1991 and worked on gene therapy for inherited diseases, particularly metabolic liver disorders.

In 1991, Dr. Grompe joined the faculty at Oregon Health & Science University and he is currently Professor in the Departments of Pediatrics and Molecular and Medical Genetics. He is a recipient of the E. Mead Johnson award for pediatric research (2002) and the Merit Award of the Fanconi Anemia Research Foundation (2002). He is involved in the clinical care of patients with genetic diseases as well as scientific investigation. In 2004 he became the first director of the newly founded Oregon Stem Cell Center. Since 2008 he is the holder of the Ray Hickey Chair and the Director of the Papé Family Pediatric Research Institute.

Research Overview

Single gene disorders, although individually rare, cumulatively represent a significant medical burden, particularly in children. Current treatment options are very limited and outcomes remain poor in many cases. Our long-term goal is to contribute to the development of novel treatments for these disorders Gene transfer and cell therapy (including stem cell transplantation) are hopeful strategies for future therapies. Our particular areas of interest are metabolic liver diseases and the DNA repair disease Fanconi Anemia. Recently, we also have developed an interest in cell transplantation for type 1 diabetes.

Metabolic Liver Disease and Therapy

The level of cell replacement required to achieve physiological benefit in the treatment of genetic liver disorders depends on which disease is being treated. The threshold can be as low as only 1% in the hemophilias or as high as 50% in urea cycle disorders. Even the low threshold is difficult to achieve with cell therapy or integrating gene transfer vectors required for life-long therapy. Fortunately, the liver is a highly regenerative organ and in mutant backgrounds where genetically normal hepatocytes have a selective advantage, extensive repopulation can be achieved. We first showed in fumarylacetoacetate hydrolase (Fah) deficient mice that cell replacement levels can reach levels of >98% illustrating the concept of "therapeutic liver repopulation".

We are tackling the problem of genetic liver disease from multiple angles, including 1) isolation and characterization of adult liver stem cells (oval cells); 2) propagation of mature hepatocytes by in vivo expansion; 3) studies on the basic biology of hepatocyte mitosis (octaploid division shown at left); 4) generation of hepatocytes from pluripotent stem cells, especially IPSC; 5) development of strategies to correct point mutations in the liver in vivo (gene repair) and 6) development of novel adeno-associated vectors capable of site-specific integration in vivo. We are considered international leaders in liver stem cell biology and hepatocyte biology.

Diabetes Cell Therapy:

Our lab has had a long-standing interest in the interrelationship between progenitor cells in the liver and the pancreas. In 2001 we showed that cells from the adult pancreas could give rise to hepatocytes in vivo. More recently, we have been focused on converting hepatobiliary cells to the pancreatic endocrine lineage using genetic reprogramming strategies. To facilitate these studies, our lab has developed novel monoclonal antibodies which permit the isolation of all known cell types from the adult liver and pancreas, both human and mouse. These reagents are giving us the opportunity to study highly pure cell populations from these tissues using genomic approaches and leverage these insights for more efficient reprogramming strategies.

This laboratory is interested in the basic defect in FA cells and therapeutic approaches. We have made murine of FA by knocking out FANCC, FANCA and FANCD2. FANCD2 deficient mice mimic several relevant features of human FA, including hematopoietic defects and cancer susceptibility. These animals have been used for genetic studies as well as preclinical therapy. Gene therapy experiments in murine models of FA have been used to demonstrate in vivo selection at the level of hematopoietic stem cells. Recently, the Grompe lab has discovered small molecules to prevent solid tumors in this disease.
Our current research is aimed at identifying novel drugs to ameliorate the hematopoietic defects. Towards this end we have developed induced pluripotent stem cells (IPSC) from FA patients and are studying hematopoiesis in FA at the stem cell level.